New perspectives in signaling mediated by receptors coupled to stimulatory G protein: the emerging significance of cAMP eï¬„ux and extracellular cAMP-adenosine pathway

Godinho, Rosely Oliveira; Duarte, Thiago; Pacini, Enio Setsuo Arakaki

doi:10.3389/fphar.2015.00058

Cited by 74 publications

(41 citation statements)

References 95 publications

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“…Gas is known to induce cAMP by activating adenylate cyclase (Godinho et al, 2015). Gai can contribute in inducing cytosolic Ca 2+ and in suppressing cAMP levels (Chow and Davis, 2000; Lee et al, 2007; Scott et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

PAR2-Mediated cAMP Generation Suppresses TRPV4-Dependent Ca2+ Signaling in Alveolar Macrophages to Resolve TLR4-Induced Inflammation

et al. 2019

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SUMMARY Alveolar macrophages (AMs), upon sensing pathogens, trigger host defense by activating toll-like receptor 4 (TLR4), but the counterbalancing mechanisms that deactivate AM inflammatory signaling and prevent lethal edema, the hallmark of acute lung injury (ALI), remain unknown. Here, we demonstrate the essential role of AM protease-activating receptor 2 (PAR2) in rapidly suppressing inflammation to prevent long-lasting injury. We show that thrombin, released during TLR4-induced lung injury, directly activates PAR2 to generate cAMP, which abolishes Ca2+ entry through the TRPV4 channel. Deletion of PAR2 and thus the accompanying cAMP generation augments Ca2+ entry via TRPV4, causing sustained activation of the transcription factor NFAT to produce long-lasting TLR4-mediated inflammatory lung injury. Rescuing thrombin-sensitive PAR2 expression or blocking TRPV4 activity in PAR2-null AMs restores their capacity to resolve inflammation and reverse lung injury. Thus, activation of the thrombin-induced PAR2-cAMP cascade in AMs suppresses TLR4 inflammatory signaling to reinstate tissue integrity.

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Section: Discussionmentioning

confidence: 99%

PAR2-Mediated cAMP Generation Suppresses TRPV4-Dependent Ca2+ Signaling in Alveolar Macrophages to Resolve TLR4-Induced Inflammation

et al. 2019

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“…It is also possible that extracellular cAMP could function via G protein-coupled receptors (GPCRs) on basal gut membranes to induce invagination. cAMP can activate GPCRs directly (Miranda et al, 2015) or can first be metabolized extracellularly to adenosine (Godinho et al, 2015). In Dictyostelium development, cAMP secreted by ABC transporters stimulates chemotaxis (Miranda et al, 2015), and chemotaxis is an important mechanism of cell movement during deuterostome gastrulation (Dormann and Weijer, 2006).…”

Section: How Does C5a In Pigment Cells Affect the Position Of The Hinmentioning

confidence: 99%

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

et al. 2015

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ATP-binding cassette (ABC) transporters are evolutionarily conserved proteins that pump diverse substrates across membranes. Many are known to efflux signaling molecules and are extensively expressed during development. However, the role of transporters in moving extracellular signals that regulate embryogenesis is largely unexplored. Here, we show that a mesodermal ABCC (MRP) transporter is necessary for endodermal gut morphogenesis in sea urchin embryos. This transporter, Sp-ABCC5a (C5a), is expressed in pigment cells and their precursors, which are a subset of the non-skeletogenic mesoderm (NSM) cells. C5a expression depends on Delta/Notch signaling from skeletogenic mesoderm and is downstream of Gcm in the aboral NSM gene regulatory network. Long-term imaging of development reveals that C5a knockdown embryos gastrulate, but ∼90% develop a prolapse of the hindgut by the late prism stage (∼8 h after C5a protein expression normally peaks). Since C5a orthologs efflux cyclic nucleotides, and cAMP-dependent protein kinase (Sp-CAPK/PKA) is expressed in pigment cells, we examined whether C5a could be involved in gastrulation through cAMP transport. Consistent with this hypothesis, membrane-permeable pCPT-cAMP rescues the prolapse phenotype in C5a knockdown embryos, and causes archenteron hyper-invagination in control embryos. In addition, the cAMP-producing enzyme soluble adenylyl cyclase (sAC) is expressed in pigment cells, and its inhibition impairs gastrulation. Together, our data support a model in which C5a transports sAC-derived cAMP from pigment cells to control late invagination of the hindgut. Little is known about the ancestral functions of ABCC5/MRP5 transporters, and this study reveals a novel role for these proteins in mesoderm-endoderm signaling during embryogenesis.

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“…Regarding the intracellular mechanism of incretins, the specific receptors for GIP or GLP-1, which belong to GTP-binding protein-coupled receptors, couple to adenylyl cyclase-activating Gs, leading to the production of cAMP (23). With regard to osteoblasts, it has been reported that both GIP and GLP-1 truly increase the intracellular cAMP levels (15).…”

Section: Discussionmentioning

confidence: 99%

Attenuation by incretins of thyroid hormone-stimulated osteocalcin synthesis in osteoblasts

et al. 2016

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Abstract. Incretins, the polypeptide hormone glucosedependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) secreted from the small intestine after nutrient ingestion, are generally known to stimulate insulin secretion from pancreatic β-cells. We previously demonstrated that triiodothyronine (T 3 ) stimulates osteocalcin synthesis at least in part through p38 mitogen-activated protein kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effects of GIP and GLP-1 on T 3 -stimulated osteocalcin synthesis and the mechanism of action involved in MC3T3-E1 cells. GIP and GLP-1 markedly suppressed the T 3 -stimulated osteocalcin release. GIP and GLP-1 significantly attenuated the expression levels of osteocalcin mRNA induced by T 3 . The T 3 -stimulated transactivation activity of the thyroid hormone-responsive element was reduced by GIP and GLP-1. These results suggest that incretins repressed the T 3 -stimulated osteocalcin synthesis in osteoblast-like MC3T3-E1 cells, and the suppressive effect of incretins was mediated through transcriptional levels.

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New perspectives in signaling mediated by receptors coupled to stimulatory G protein: the emerging significance of cAMP eï¬„ux and extracellular cAMP-adenosine pathway

Cited by 74 publications

References 95 publications

PAR2-Mediated cAMP Generation Suppresses TRPV4-Dependent Ca2+ Signaling in Alveolar Macrophages to Resolve TLR4-Induced Inflammation

PAR2-Mediated cAMP Generation Suppresses TRPV4-Dependent Ca2+ Signaling in Alveolar Macrophages to Resolve TLR4-Induced Inflammation

ABCC5 is required for cAMP-mediated hindgut invagination in sea urchin embryos

Attenuation by incretins of thyroid hormone-stimulated osteocalcin synthesis in osteoblasts

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